The Role of the Cardiomyocyte HIF pathway and FOG2 in Coronary Microvascular Disease

心肌细胞HIF通路和FOG2在冠状动脉微血管疾病中的作用

• 批准号: 9897548
• 负责人: Marie A Guerraty
• 金额: $ 16.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897548
• 关键词: Academic Medical Centers; Achievement; Address; Adult; Advisory Committees; Affect; Anaerobic Bacteria; Angiogenic Factor; Award; Biological Markers; Blood capillaries; Blood flow; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Culture Techniques; Cell Respiration; Cells; Coronary; Coronary Arteriosclerosis; Coronary heart disease; DNA; Data; Development; Diabetic mouse; Disease; EFRAC; Environment; Fatty Acids; Friends; Functional Imaging; Functional disorder; GATA4 gene; Genetic; Goals; Health Care Costs; Heart; Heart Diseases; Heart failure; Histologic; Human; Hypoxia; Hypoxia Inducible Factor; Immune; In Vitro; Infiltration; Ischemia; Knockout Mice; Maintenance; Mediating; Medicine; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Microvascular Dysfunction; Mitochondria; Morbidity - disease rate; Mus; Myocardial; Myocardial perfusion; Myocardial tissue; Pathology; Pathway interactions; Patients; Perfusion; Phenotype; Physicians; Plasma; Play; Procollagen-Proline Dioxygenase; Research; Research Proposals; Role; Scientist; Signal Transduction; Structure; Therapeutic; Tissue Sample; Transcription Coactivator; Up-Regulation; VEGFA gene; adeno-associated viral vector; angiogenesis; arteriole; base; biobank; career; cohort; conditional knockout; density; direct application; evidence base; experimental study; genetic variant; glucose metabolism; heart metabolism; improved; in vivo; innovation; mortality; mouse model; novel; novel therapeutics; preservation; programs; response; targeted treatment; therapeutic target; transcription factor

PROJECT SUMMARY Coronary microvascular disease (CMVD), or disease of the coronary pre-arterioles, arterioles, and capillaries, has become an increasingly well-recognized cardiac pathology, which carries a high burden of morbidity, healthcare costs, and increased mortality. CMVD exists in isolation and also exacerbates other cardiac disease such as coronary artery disease (CAD) and cardiomyopathies. In addition, the pathophysiology of CMVD also has implications for heart failure with preserved ejection fraction (HFpEF) and coronary collateral formation. The Hypoxia-Inducible Factor 1a (HIF) pathway is activated in response to hypoxia and has been studied in the context of coronary microvasculature and cardiac perfusion. Signaling through the HIF pathway promotes angiogenesis and may improve microvascular structure, however, the HIF pathway is known to have deleterious metabolic effects on cardiomyocytes. Uncoupling the beneficial angiogenic and deleterious metabolic effects of the HIF pathways would therefore be highly beneficial. Evidence that FOG2, a transcriptional co-activator of GATA4, is a key regulator of coronary development and the maintenance of coronary microvasculature into adulthood, have led to the novel hypothesis that FOG2 is a critical regulator in the HIF pathway and that FOG2 can mediate HIF-induced coronary angiogenesis without deleterious effects on cardiac metabolism. I have developed a translational framework consisting of 1) a mouse model of CMVD and 2) functional imaging of the mouse coronary microvasculature to help investigate this hypothesis. Three interrelated Specific Aims will address the hypothesis: 1) Characterize HIF-induced angiogenesis and metabolic changes in cardiomyocytes and determine whether FOG2 mediates HIF induction of angiogenic and metabolic pathways in cardiomyocyte cell culture; 2) Delineate the role of HIF and FOG2 pathways in CMVD and determine whether FOG2 mediates HIF induction of coronary angiogenesis without affecting cardiac metabolism in mice; and 3) Define the role of the HIF and FOG2 pathways in CMVD in humans. The experiments in this innovative proposal will also have direct application toward the development of novel therapies for CMVD. In addition, the research proposal is supported in an integrated manner through exceptional mentorship, a research advisory committee filled with relevant expertise, and unequivocal divisional and institutional commitment. Finally, this K08 award will serve as a basis for the achievement of my ultimate career goal to become an independent physician-scientist at a major academic medical center.

项目摘要 冠状动脉疾病（CMVD）或冠状动脉前，小动脉和毛细血管的疾病， 已经成为一种越来越公认的心脏病理学，带来了高度的发病负担， 医疗保健费用和增加死亡率。 CMVD孤立地存在，也加剧了其他心脏病 例如冠状动脉疾病（CAD）和心肌病。另外，CMVD的病理生理学也 对心力衰竭的意义，保留的射血分数（HFPEF）和冠状动脉侧支形成。 低氧诱导因子1a（HIF）途径是针对缺氧而激活的，并且已在 冠状动脉微举行和心脏灌注的背景。通过HIF途径传导促进 血管生成并可能改善微血管结构，但是，已知HIF途径具有 对心肌细胞的有害代谢作用。解开有益的血管生成和有害的 因此，HIF途径的代谢作用将是非常有益的。证据表明fog2，一个 GATA4的转录共激活剂是冠状动脉发育的关键调节剂，维护 成年后的冠状动脉微脉管系统导致了新的假设，即Fog2是关键的调节剂 在HIF途径中，Fog2可以介导HIF诱导的冠状动脉生成而无需有害 对心脏代谢的影响。我已经开发了一个由1）鼠标模型组成的翻译框架 CMVD和2）小鼠冠状动脉微脉管系统的功能成像，以帮助研究这一假设。 三个相互关联的特定目的将解决以下假设：1）表征HIF诱导的血管生成和 心肌细胞的代谢变化，并确定FOG2是否介导HIF诱导血管生成和 心肌细胞培养中的代谢途径； 2）描述HIF和FOG2途径在CMVD中的作用 并确定FOG2是否介导HIF诱导冠状血管生成而不影响心脏 小鼠的代谢； 3）定义了HIF和FOG2途径在人类中CMVD中的作用。这 该创新提案中的实验也将直接应用于新颖的发展 CMVD的疗法。此外，通过综合方式支持研究建议 杰出的指导，一个充满相关专业知识的研究咨询委员会和明确的指导委员会 部门和机构承诺。最后，该K08奖将是实现我的基础 成为主要学术医学中心的独立医师科学家的最终职业目标。